The major objective of this project, and that of the Research Division of the Center on Alcoholism, Substance Abuse, and Addictions (CASAA), is the systematic extension and integration of previous research with the development of new knowledge on the effectiveness of alternative approaches to the treatment of alcohol and other drug problems. A second goal and central theme is the determination of individual difference markers of response to specific treatments ('matching') within a racially diverse population. A third goal is the integration of principles, methods and findings from the areas of preclinical animal models of ethanol drinking and reinforcement with those from human clinical studies on alcoholism treatment. These aims will be achieved through the completion of an extended double-blind, placebo-controlled trial of the effectiveness of sertraline (Zoloft), a selective serotonin uptake inhibitor, as an adjunctive treatment for alcohol problems. During this project, we will determine the extent to which manipulation of serotonergic function via sertraline can enhance the effects of representative psychosocial treatment for alcohol problems. However, because the mechanism by which blockade of serotonin uptake causes reductions in alcohol intake is not well understood, the study design incorporates covariates useful in testing alternative causal hypotheses. In this way, the design will permit conclusions regarding riot only the overall magnitude and nature of sertraline's impact on drinking behavior after treatment, but the process measures which mark this response, suggesting possible causal mechanisms. This includes concurrent study of the effects of sertraline on alternative reinforcers such as food and tobacco, on general appetitive and motivational behavior, and on a number of physiological responses to the specific pharmacotherapy. The design of this study will also allow us to determine the characteristics of individuals who show larger specific responses to this pharmacologic agent, suggesting criteria for future matching, particularly with regard to specific ethnic and gender groups. Thus, the results of this study will substantially increase our understanding of the mechanisms of uncontrolled alcohol drinking in humans while providing a direct test of the efficacy of a potentially important adjunctive pharmacotherapy for use in the treatment of alcohol related problems.